The matrix metalloprotease (MMP) family of zinc endoproteases includes fibroblast collagenase (MMP-1, collagenase-1), neutrophil collagenase (MMP-8, collagenase-2), chondrocyte collagenase (MMP-13, collagenase-3), gelatinases A and B (MMP's 2 and 9), and members of the stromelysin family such as stromelysin-1 (MMP-3), stromelysin-3 (MMP-11), and matrilysin (MMP-7). These enzymes accelerate breakdown of connective tissue by catalyzed resorption of the extracellular matrix. This is a feature of diverse pathologies; therefore, inhibitors of one or more of the matrix metalloproteases would have utility in a wide range of disease states such as in abrogating the initiation of tumor metastasis and angiogenesis and in halting the pathogenesis of demyelinating diseases of the nervous system, multiple sclerosis being one example. MMP inhibitors would also find utility in diseases involving connective tissue degradation in the joint, as occurs in osteoarthritis and rheumatoid arthritis. MMP's-1 and -3 have been found in elevated levels in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis.
Collagenase-3 (MMP-13) is a member of the family of MMP's which preferentially digest collagen. Collagenase-3 is one of the more newly characterized MMP's; biochemical studies on the recombinant protein have demonstrated that it cleaves type II collagen, the predominant matrix component of articular cartilage, more efficiently than either MMP-1 or MMP-2 and that it is expressed by chondrocytes in osteoarthritic cartilage. These data would implicate collagenase-3 as a significant target in rheumatoid arthritis and osteoarthritis for inhibition by MMP inhibitors.
Compounds which inhibit the activities of one or more of the matrix metalloproteases are recognized as having therapeutic benefit in one or more pathologies where MMP activity is upregulated, such as:
i) inflammatory/autoimmune diseases, including but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases, periodontal disease, gingivitis, and corneal ulceration; PA1 ii) cardiovascular diseases, including but not limited to atherosclerosis and restenosis; PA1 iii) metabolic diseases, including but not limited to complications of diabetes, osteoporosis, and other disorders involving resorption of bone; PA1 iv) neurologic diseases, including but not limited to multiple sclerosis and other demyelination ailments; PA1 v) diseases of cancer and malignancy, including but not limited to cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix uteri, corpus endometrium, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, brain and central nervous system, thyroid and other endocrine gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, tumor invasion, and metastatic and angiogenic events thereof; PA1 vi) renal diseases, including but not limited to nephrotic syndromes and glomerulonephritis; and PA1 vii) infectious diseases, including but not limited to those mediated by viruses, bacteria, and fungi; PA1 viii) respiratory diseases, including but not limited to emphysema and COPD. PA1 i) inflammatory/autoimmune diseases, including but not limited to rheumatoid arthritis, osteoartritis, Crohn's disease and other inflammatory bowel diseases and inflammatory gastrointestinal diseases, and systemic lupus erythematosis; PA1 ii) reperfusion injuries, such as those caused by an initial ischemic event; PA1 iii) systemic inflammatory response syndromes, including but not limited to sepsis, burn injury, pancreatitis, and adult respiratory distress syndrome; PA1 iv) allergic and dermatologic diseases, including but not limited to delayed type hypersensitivity, psoriasis, asthma, eczema, allergic rhinitis, and allergic conjunctivitis; PA1 v) cardiovascular diseases, including but not limited to hyperlipidemia, myocardial infarction, atherosclerosis, chronic obstructive pulmonary disease, and restenosis; PA1 vi) metabolic diseases, including but not limited to osteoporosis, obesity, and diabetes; PA1 vii) neurologic diseases, including but not limited to Alzheimer's disease, Parkinson's disease, multiple sclerosis, aneurism, and stroke; PA1 viii) transplant rejection, including but not limited to organ transplant rejection and graft versus host disease; PA1 ix) diseases of cancer and malignancy, including but not limited to cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, rectum, breast, cervix uteri, corpus endometrium, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, brain and central nervous system, thyroid and other endocrine gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, tumor invasion, and metastatic and angiogenic events thereof, PA1 x) renal diseases, including but not limited to nephrotic syndromes and glomerulonephritis; PA1 xi) cachexia and related wasting syndromes; PA1 xii) infectious diseases, including but not limited to HIV infection and neuropathy, Epstein-Barr viral infection, herpes viral infection, malaria, meningitis, schistosomiasis, leprosy, hepatitis (which includes hepatitis A, hepatitis B, and hepatitis C), infectious arthritis, leishmaniasis, tuberculosis, Lyme disease, and viral encephalitis; PA1 xiii) effects of disease therapy, including but not limited to cytokine therapy, chemotherapy, radiation therapy and therapies using anti-T-cell antibodies or cytotoxin-antibody conjugates; and PA1 xiv) ocular diseases, including but not limited to diabetic retinopathy and macular degeneration. PA1 where R.sub.1 is ##STR4## PA1 where A.sub.1 is alkylene, alkenylene, alkynylene, or a direct bond; PA1 A.sub.2 is O, S, SO, SO.sub.2, or a direct bond; PA1 A.sub.3 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, or hydrogen; PA1 where D.sub.1 is ##STR6## PA1 D.sub.2 is alkylene, alkenylene, alkynylene, or a direct bond, PA1 D.sub.3 is cycloalkylene, cycloalkenylene, heterocyclylene, arylene, hetereroarylene, or a direct bond, PA1 D.sub.4 is alkyl, aryl, heteroaryl, or hydrogen; PA1 where E.sub.1 is alkylene, alkenylene, alkynylene, or a direct bond, PA1 E.sub.2 is S, O, SO, SO.sub.2, C(O)O, OC(O), NR.sub.7, C(O)NR.sub.7, NR.sub.7 C(O), SO.sub.2 NR.sub.7, or a direct bond, where R.sub.7 is as defined below; PA1 E.sub.3 is alkylene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond; PA1 E.sub.4 is ##STR8## PA1 E.sub.5 is lower alkyl or hydrogen; PA1 where Z.sub.1 is heteroarylene or a direct bond; PA1 Z.sub.2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR.sub.8 R.sub.9, OR.sub.8, or hydrogen, where R.sub.8 and R.sub.9 are as defined below; and PA1 W is a reverse hydroxamic acid group; PA1 R.sub.1 is a substituent other than hydrogen; PA1 R.sub.4 is a lipophilic substituent containing a nitro--substituted guanidine group, and; PA1 R.sub.6 is hydrogen, or an alkyl or heteroaryl substituent. PA1 R.sub.1 is ##STR12## PA1 A.sub.1 is alkylene, alkenylene, alkynylene, or a direct bond; PA1 A.sub.2 is O, S, SO, SO.sub.2, or a direct bond; PA1 A.sub.3 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, or hydrogen; PA1 D.sub.1 is ##STR14## PA1 D.sub.2 is alkylene, alkenylene, alkynylene, or a direct bond, PA1 D.sub.3 is cycloalkylene, cycloalkenylene, heterocyclylene, arylene, hetereroarylene, or a direct bond, PA1 D.sub.4 is alkyl, aryl, heteroaryl, or hydrogen; PA1 E.sub.1 is alkylene, alkenylene, alkynylene, or a direct bond, PA1 E.sub.2 is S, O, SO, SO.sub.2, C(O)O, OC(O), NR.sub.7, C(O)NR.sub.7, NR.sub.7 C(O), SO.sub.2 NR.sub.7, or a direct bond, where R.sub.7 is as defined below; PA1 E.sub.3 is alkyene, cycloalkylene, cycloalkenylene, arylene, heterocyclylene, heteroarylene, or a direct bond; PA1 E.sub.4 is ##STR16## PA1 E.sub.5 is lower alky or hydrogen; PA1 Z.sub.1 is heteroarylene or a direct bond; PA1 Z.sub.2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl, NR.sub.8 R.sub.9, OR.sub.8, or hydrogen, where R.sub.8 and R.sub.9 are as defined below; PA1 R.sub.7, R.sub.8, and R.sub.9 are, independently, hydrogen, alkyl, alkynyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl; PA1 R.sub.1 is methyl, trifluoromethyl, ethyl, phenylsulfanylmethyl, phenylsulfonylmethyl, thiophene-2-sulfanylmethyl, thiophene-2-sulfonylmethyl, isopropyl, 3-methyl-1-butyl, benzylmethyl, 2-benzyloxy-1-ethyl, benzyl, n-propyl, 3,3,3-trifluoro-1-propyl, or cycloprpyl; PA1 R.sub.2 is isobutyl, cyclohexylmethyl, 3-(2-furyl)-1-propyl, 3-(4-biphenyl)-1-propyl, 4-methylcycohexylmethyl, cycloheptylmethyl, cyclohexyl, 5-methylthiophene-2-methyl, 4-phenyl-1-butyl, 3-phenyl-1-propyl, or benzyl; PA1 R.sub.3 is hydrogen, methyl, or ethyl; PA1 R.sub.4 is 3-(nitroimino-amino)methylamino-1-propyl, 3-(nitroimino-amino)methyl-ethlamino-1-propyl, 3-(nitroimino-amino)methyl-methylamino-1-propyl, 3-(nitroiminohyl-amino)methyl-isopropylamino-1-propyl, 2-(nitroimino-amino)methylamino-1-ethylaminocarbonylethyl, 2-(nitroimino-amino)methylamino-1-ethylaminocarbonylmethyl, 4-(nitroimino-amino)methylamino-1-butyl, or 4-(nitroimino-amino)methylamino-2-butyl; PA1 R.sub.5 is hydrogen, methyl, ethyl, or n-propyl; and PA1 R.sub.6 is hydrogen, methyl, 5-ethyl-2-thiazolyl, cyclopropyl, cyclobutyl, cycloheptyl, 2,2,2-trifluoroethyl, cyclopentyl, 3-cyclopenten-1-yl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, or 2-thiazolyl. PA1 R.sub.1 is methyl, isopropyl, benzyl, n-propyl, 3,3,3-trifluoro-1-propyl, or cyclopropyl; PA1 R.sub.2 is isobutyl, cyclohexylmethyl, 4-methylcyclohexylmethyl, 5-methylthiophene-2-methyl, 3-phenyl-1-propyl, or benzyl; PA1 R.sub.3 is hydrogen; PA1 R.sub.4 is 3-(nitroimino-amino)methylamino-1-propyl, or 4-(nitroimino-amino)methylamino-2-butyl; PA1 R.sub.5 is hydrogen; and PA1 R.sub.6 is hydrogen, methyl, or 2-thiazolyl. PA1 R.sub.1 is methyl, n-propyl, or 3,3,3-trifluoro-1-propyl; PA1 R.sub.2 is isobutyl, 3-phenyl-1-propyl, or benzyl; PA1 R.sub.3 is hydrogen; PA1 R.sub.4 is 3-(nitroimino-amino)methylamino-1-propyl; PA1 R.sub.5 is hydrogen; and PA1 R.sub.6 is hydrogen, methyl, or 2-thiazolyl. PA1 R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are defined as for formula (II). PA1 RPG.sub.1 is a protecting group suitable for the hydroxylamine oxygen, such as benzyl or 2-tetrahydropyranyl. PA1 R.sub.10 is chosen from the group consisting of hydroxyl, O--C.sub.6 F.sub.5, or halogen. PA1 R.sub.1 and R.sub.2 are as defined for formula (II). PA1 R.sub.11 O is a nucleofugal group such as methanesulfonate or p-toluenesulfonate. PA1 RPG.sub.1 is as defined for reaction Scheme 1. PA1 R.sub.1 and R.sub.2 are as defined as for formula (II). PA1 R.sub.12, R.sub.13, R.sub.14, and R.sub.15 may be, independently, alkyl, alkenyl, alkynyl, or hydrogen. PA1 R.sub.16 is selected from the group consisting of aryl, heteroaryl, alkynyl, or alkenyl, with the proviso that the unsaturated carbons of alkenyl and alkynyl groups are directly bonded to L.sub.1. PA1 L.sub.1 is selected from the group consisting of bromide, iodide, or trifluoromethanesulfonate. PA1 L.sub.2 is tri(lower alkyl)stannyl or --B(OH).sub.2. PA1 RPG.sub.1 is defined as for reaction scheme 1. PA1 R.sub.1 and R.sub.2 are as defined as for formula (II). PA1 R.sub.17 is lower alkoxy or 1-oxazolidinyl. PA1 RPG.sub.1 is as defined for reaction Scheme 1. PA1 R.sub.1 and R.sub.2 are as defined for formula (II). PA1 R.sub.20 is lower alkyl. PA1 RPG.sub.1 is as defined for reaction Scheme 1. PA1 L.sub.3 is bromide, iodide, or trifluoromethanesulfonyloxy. PA1 R.sub.12, R.sub.13 and R.sub.14 are as defined for reaction scheme 3. PA1 R.sub.18 and R.sub.19, may be, independently, alky, alkenyl, alkynyl, or hydrogen. PA1 R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined for general formula (II). PA1 RPG.sub.2 is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl. PA1 R.sub.21 is hydroxyl or halogen. PA1 R.sub.3, R.sub.4, E.sub.1, E.sub.2, E.sub.3, and E.sub.5 are as defined for general formula (II). PA1 RPG.sub.2 is defined as for reaction scheme 6. PA1 R.sub.22 is lower alkyl. PA1 R.sub.3, R.sub.4, E.sub.1, E.sub.3, and R.sub.7 are as defined for general formula (II). PA1 R.sub.24 is SH, NR.sub.7, or OH. PA1 E.sub.6 is S, NR.sub.7, OC(O), or O. PA1 RPG.sub.2 is defined as for reaction scheme 6. PA1 R.sub.22 is defined as for reaction scheme 7. PA1 R.sub.23 is bromide, iodide, methanesulfonate, or p-toluenesulfonate. PA1 R.sub.24 is hydrogen. PA1 R.sub.3, E.sub.1, E.sub.2, E.sub.3, and E.sub.5 are as defined for general formula (II). PA1 E.sub.6, R.sub.23, and R.sub.24 are defined as for reaction scheme 8. PA1 RPG.sub.2 is defined as for reaction scheme 6. PA1 R.sub.22 is defined as for reaction scheme 7. PA1 RPG.sub.3 is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl. PA1 R.sub.3, R.sub.4, R.sub.7, E.sub.1, E.sub.3, and E.sub.5 are as defined for general formula (II). PA1 RPG.sub.2 is defined as for reaction scheme 6. PA1 R.sub.22 is defined as for reaction scheme 7. PA1 RPG.sub.3 is defined as for reaction scheme 9. PA1 R.sub.3, R.sub.4, R.sub.7, E.sub.1, E.sub.3, and E.sub.5 are as defined for general formula (II). PA1 RPG.sub.2 is defined as for reaction scheme 6. PA1 R.sub.22 is defined as for reaction scheme 7. PA1 RPG.sub.3 is defined as for reaction scheme 9. PA1 R.sub.3, R.sub.4, R.sub.7, E.sub.1, E.sub.2, E.sub.3, and E.sub.5 are as defined for general formula (II). PA1 RPG.sub.2 is defined as for reaction scheme 6. PA1 R.sub.22 is defined as for reaction scheme 7. PA1 R.sub.25 is alkcyl, alkenyl, alkynyl, cycloalkyl, or hydrogen. PA1 R.sub.26 and R.sub.27 are, independently, alkyl, alkenyl, or alkynyl. PA1 R.sub.28 is O or NH. PA1 R.sub.25 and R.sub.27 may be taken together to constitute a five to ten--membered ring. PA1 R.sub.26 and R.sub.27 may be taken together to constitute a five to ten--membered ring. PA1 R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined for general formula (II). PA1 R.sub.29 is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, arylene, or heteroarylene.
Many inhibitors of matrix metalloproteases have been disclosed, including some structure activity relationships for a series of carboxylalkylamine inhibitors. These molecules are exemplary for MMP inhibitors in general. They generally embody a functional group capable of tightly binding the zinc cofactor at the enzyme active site, which is contained within a peptidic or pseudopeptide structure. Zinc binding groups among the MMP inhibitor art have included hydroxamic acid, reverse hydroxamic acid, thiol, carboxylate, and phosphinate.
Hydroxamate metalloprotease inhibitors disclosed in the art usually have the following general structure (I): ##STR2##
where W is a zinc-chelating acyl derivative group of the formula --C(O)NHOH (which by convention and in this application are referred to as "forward hydroxamates") or a zinc-chelating substituted amine group of the formula --NH(OH)C(O)R (which by convention and in this application are referred to as "reverse hydroxamates"), where R is usually hydrogen or alkyl. The other substituents vary according to specifications expressed by the art disclosure. It is understood and demonstrated that variations in these substituents can have dramatic effects on potency and selectivities between the matrix metalloproteases.
Suppression of MMP activity in conditions characterized by its overproduction would be of benefit, and compounds which inhibit MMP's would act in this manner at a specific target and be useful and of benefit. The present invention fills this need by providing potent, specific, orally or parenterally active inhibitors of matrix metalloproteases.
Tumor necrosis factor-.alpha. (TNF.alpha.), hereinafter called "TNF", is a mammalian protein capable of inducing cellular effects by virtue of its interaction with specific cellular receptors. It was initially characterized and so named due to its ability to cause death of cancerous cells. It is produced primarily by activated monocytes and macrophages. Human TNF is produced as a larger pro-form of 26 kD which is processed to a secreted 17 kD mature form by proteolytic processing of the alanine-76--valine-77 peptide bond.
Recently, certain compounds having matrix metalloprotease--inhibiting activity have been found to inhibit the release of mature 17 kD TNF from cells. Further, these inhibitors also protect mice from a lethal dose of endotoxin indicating that the compounds can inhibit TNF secretion in vivo. These compounds inhibit the cell-associated proteolytic processing of the 26 kD pro-TNF to the mature 17 kD form. The proteolytic activity is thought to reside in an intracellular or cell-associated specific enzyme or family of enzymes, which by convention is called a "TNF convertase", distinct from the matrix metalloproteases but related in that both contain a zinc cation at the active site. TNF convertase enzymatic activity can be detected in monocyte membrane fractions, and the enzyme activity can be inhibited by certain matrix metalloprotease--inhibiting compounds.
A metalloprotease is thought to mediate the proteolysis of the cell--surface IgE receptor CD23. Certain of the CD23--derived peptides possess proinflammatory biological activities mimicking those of cytokines, including TNF.alpha..
Metalloprotease--like activity is also thought to contribute to the shedding of certain cell surface protein ectodomains such as L-selectin, fibronectin, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density lipoprotein receptor, beta amyloid precursor protein, interleukin-6 receptor alpha subunit, Fas ligand, CD40 ligand, epidermal growth factor receptor, macrophage colony stimulating factor, interleukin-1 receptor type II, CD30, and tumor necrosis factor receptors type I and II.
TNF is known to mediate many biological responses in vivo. Preclinical and clinical studies in animals and humans with specific TNF neutralizing antibodies, soluble TNF receptor constructs, and TNF detection techniques have implicated TNF as a mediator in numerous pathologies. The compounds of the present invention by virtue of their activity in inhibiting TNF production and/or their activity in preventing cell surface protein ectodomain shedding should show utility in the treatment of diverse pathologies such as;
Suppression of TNF activity in conditions characterized by its overproduction would be of benefit, and compounds which inhibit TNF convertase would act in this manner at a specific target and be useful and of benefit. The present invention fulfills this need by providing potent, specific, orally or parenterally active inhibitors of matrix metalloproteases, including potent, specific, orally or parenterally active inhibitors of TNF-alpha release from monocyte cells acting via inhibition of TNF-alpha converting enzyme (TNFc).
Suppression of shedding of cell surface protein ectodomains in conditions characterized by an overactivity of such a shedding enzyme or enzymes would be of benefit, and compounds which inhibit this cell surface protein ectodomain shedding would be useful and of benefit. The present invention fulfills this need by providing potent, orally or parenterally active inhibitors of shedding of cell surface protein ectodomains acting via inhibition of one or more specific enzymes which mediate this proteolytic event.
Furthermore, as described above, suppression of CD23 proteolysis in conditions characterized by an overabundance of CD23 proteolytic fragments would be of benefit, and compounds which inhibit CD23 proteolysis would be useful and of benefit. The present invention fulfills this need by providing potent orally or parenterally active inhibitor of CD23 proteolysis acting via inhibition of one or more specific enzymes which mediate this proteolytic event.